1. Field of the Invention
The novel and useful formulations of the antibiotic 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5- ylthiomethyl)-3-cephem-4-carboxylic acid provided by the present invention possess in general the usual attributes of the cephalosporin family of antibacterial agents and are particularly useful in the treatment of bacterial infections by injection.
2. Description of the Prior Art
The preparation of the compound 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5- ylthiomethyl)-3-cephem-4-carboxylic acid having the formula ##STR1## has been described in German published application No. 2,364,192 (corresponding to U.S. application Ser. No. 318,340 filed Dec. 26, 1972) and also in U.S. Pat. No. 3,867,380 which issued Feb. 18, 1975. The compound is therapeutically effective against infections caused by both Gram-positive and Gram-negative organisms, and it may be administered both orally and parenterally.
The known pharmaceutical forms of the compound of formula I, including the zwitterion free acid form disclosed in the above-mentioned U.S. Ser. No. 318,340, the zwitterion 1,2- propylene glycolate disclosed in U.S. application Ser. No. 431,251 filed Jan. 7, 1974 and the zwitterion hydrate forms disclosed in U.S. application Ser. No. 473,039 filed May 24, 1974 cannot be administered intravenously because of their relatively low solubility in water.
Attempts to prepare stable, water-soluble salts of compound I which could be employed in providing solutions for injection have not been successful. The alkali metal salts of compound I have sufficient solubility in water to provide true solutions necessary for intravenous administration but, unfortunately, all attempts at preparing these salts, e.g., by reaction of an alkali metal hydroxide with the cephalosporin free acid in an aqueous reaction medium, have resulted in rapid inactivation of the antibiotic. The problem of preparing suitable water-soluble salts of compound I has been especially complicated since in addition to the normal .beta.-lactam instability at higher pH ranges, the triazole moiety at the 3-position of cephalosporin I is found to split off rapidly at alkaline pH, i.e. pH.about.7.0 or higher, resulting in formation of an inactive or low potency degradation product. An acid addition salt of compound I with hydrochloric acid has also been made (see Preparation of Starting Materials below). While soluble, this salt was found to result in significant venous irritation and muscle damage when administered parenterally in test animals, presumably due to the low pH of the aqueous salt solutions.
It is the object of the present invention to provide 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5- ylthiomethyl)-3-cephem-4-carboxylic acid in novel pharmaceutically acceptable forms which upon the addition of sterile water or a sterile aqueous vehicle will give true solutions of the cephalosporin antibiotic suitable for parenteral administration.
It is another object of the present invention to provide water-soluble pharmaceutical forms of cephalosporin I which have acceptable thermal stability in the solid state, which upon reconstitution with sterile water or a sterile aqueous vehicle provide true solutions of from about 10 to 350 mg. 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5- ylthiomethyl)-3-cephem-4-carboxylic acid per ml. of solution having a useful life of at least several hours at room temperature and which show freedom from excessive vein or muscle irritation upon intravenous or intramuscular administration.
It is still another object of the present invention to provide injectable aqueous solutions of compound I which (a) have a pH range of from about 3.5 to 8.0, (b) contain from about 10 to 350 mg. of compound I per ml. of solution, (c) result in freedom from excessive vein or muscle irritation upon intravenous or intramuscular administration and (d) have a useful life of at least several hours at room temperature.
It is a further object of the present invention to provide processes for preparing the water-soluble solid formulations and aqueous solutions mentioned above.
Other objects, aspects and advantages of this invention will become apparent from reading the description which follows.